In May 1999, a Licensing Agreement between Zonagen, Inc., and the NICHD was finalized to develop new 19-substituted-norprogestins. New antiprogestins (APs) discovered by NICHD and realized as drugs through this SBIR, would bring the results of government-sponsored science into the public domain. We expect that the new generation of compounds will be used for a number of indications where the etiology is dominated by progesterone. Tissues of the reproductive system such as pituitary, breast, myometrium, cervix, and endometrium remain obvious target organs for treatment with APs. Other indications could include oral contraception, postcoital contraception, labor induction, cervical ripening, hormone replacement therapy and treatment of breast cancer. The following document outlines experiments to be performed under a SBIR that would clarify the properties of these new APs and enhance their utility for the treatment of endometriosis. It is the intention of Phase I of this proposed SBIR program to determine effects on the eutopic endometrium of cynomolgus monkeys (Macaca fascicularis). We do not believe the antiprogestins could affect ectopic lesion (endometriosis) if there was no effect on eutopic endometrium. We intend to expand this program in Phase II to determine whether the same compound will reduce the size of endometriosis-like lesions in the same species. This animal model has been shown to respond to both GnRH agonists and to RU 486 with a decrease in lesion size. The use of GnRH agonists in women for the amelioration of endometriosis, although far from ideal, is one of the few medical therapies currently available. The primary outcome parameters will be alterations in the growth of eutopic/ectopic endometrium and effects on serum hormones with our lead antiprogestin compound. The secondary outcome parameter will be the effects on markers of endometriosis in peritoneal fluid. PROPOSED COMMERCIAL APPLICATIONS: Our preliminary evidence indicates that one or more of this new class of antiprogestins may be the ideal drug for treatment of endometriosis and uterine fibroids. Such compounds could fill Zonagen's developmental pipeline with drugs for those diseases and, potentially, other indications.